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Symbol report for GABRA3

Stable symbol

HGNC data for GABRA3

Approved symbol
GABRA3
Approved name

gamma-aminobutyric acid type A receptor subunit alpha3

Locus type
gene with protein product
HGNC ID
HGNC:4077
Symbol status
Approved
Previous names
gamma-aminobutyric acid (GABA) A receptor, alpha 3
Alias names
GABA(A) receptor, alpha 3
Chromosomal location
Xq28
Bos taurus
GABRA3 VGNC:29192 VGNC
Canis familiaris
GABRA3 VGNC:41055 VGNC
Equus caballus
GABRA3 VGNC:18193 VGNC
Felis catus
GABRA3 VGNC:62419 VGNC
Macaca mulatta
GABRA3 VGNC:72848 VGNC
Mus musculus
Gabra3 MGI:95615 Curated
Pan troglodytes
GABRA3 VGNC:7632 VGNC
Rattus norvegicus
Gabra3 RGD:2648
Sus scrofa
GABRA3 VGNC:88302 VGNC
IUPHAR/BPS Guide to PHARMACOLOGY
406
Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features.
Niturad CE et al. Brain 2017 Nov;140(11)2879-2894
Niturad CE, Lev D, Kalscheuer VM, Charzewska A, Schubert J, Lerman-Sagie T, Kroes HY, Oegema R, Traverso M, Specchio N, Lassota M, Chelly J, Bennett-Back O, Carmi N, Koffler-Brill T, Iacomino M, Trivisano M, Capovilla G, Striano P, Nawara M, Rzonca S, Fischer U, Bienek M, Jensen C, Hu H, Thiele H, Altmüller J, Krause R, May P, Becker F, EuroEPINOMICS Consortium, Balling R, Biskup S, Haas SA, Nürnberg P, van Gassen KLI, Lerche H, Zara F, Maljevic S, Leshinsky-Silver E.
Brain 2017 Nov;140(11)2879-2894
Abstract: Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α3-subunit of the GABAA receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α3-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.